Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

Anja Dölle, Bikash Adhikari, Andreas Krämer, Janik Weckesser, Nicola Berner, Lena Marie Berger, Mathias Diebold, Magdalena M. Szewczyk, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Jakob Gebel, Frank Löhr, Volker Dötsch, Martin Eilers, Stephanie Heinzlmeir, Bernhard Kuster, Christoph Sotriffer, Elmar Wolf, Stefan Knapp

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

Original languageEnglish
Pages (from-to)10682-10710
Number of pages29
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - 12 Aug 2021


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